Currently, attempts to use a drug carrier having a drug incorporated in a molecular assembly as a drug delivery system are actively studied, and some have already been used in clinical applications. For example, for carrying a hydrophilic drug, there has been proposed a drug carrier encapsulating such a drug in an inner aqueous phase of a bilayer vesicle formed of an assembly of phospholipid molecules, namely, a so-called liposome. For carrying a hydrophobic drug, there has been proposed a drug carrier having such a drug as being physically dissolved or chemically bound to a hydrophobic part of a molecular assembly such as, for example, a lipid microsphere which is an o/w emulsion or a micelle formed of surfactants or amphiphilic polymers. Alternatively, a hydrophobic drug may be encapsulated in a bilayer hydrophobic part of a liposome.
When such a drug carrier is administered to, for example, blood, the drug carrier is mainly taken into macrophage of organisms having a developed reticuloendothelial system (for example, spleen, liver, etc.). Therefore, the residence time of the drug carrier in blood is remarkably short. Such a drug carrier is only used when the target is such an organ. Hence, measures are taken for extending the residence time in blood. For example, a liposome modified with polyethylene glycol chains, that are water-soluble and highly biocompatible polymer, or the like is often used as a so-called Stealth liposome. This technique started by Abuchowski et al. as a study of modifying serum albumin with a polyethylene glycol chain. Already in the first half of the 1990's, adenosine deaminase and asparaginase each modified with a polyethylene glycol chain were approved for clinical use. It has been reported that modification of protein with polyethylene glycol chains provides the effects of, for example, decreasing antigenicity and increasing the ease of residing in blood.
A liposome surface-modified with a polyethylene glycol chain (PEG-liposome) can avoid being taken into a reticuloendothelial system and can reside in blood for an extended period of time. Passive targeting to a solid cancer tissue utilizing this feature is one strategy of drug delivery system.
In general, a solid cancer tissue has features that highly branched neovascularized vessels are abnormally developed and the blood vessel walls are thin and discontinuous. When size of a PEG-liposome, which can reside in blood for a long time, was 300 nm or less, it can leak out from the blood into the stroma through a highly transmissive blood vessel wall in cancer tissue. Once leaked outside, the PEG-liposome is unlikely to return toward the lumen and is accumulated. Therefore, the PEG liposome has an effect of providing the higher integration ability to a solid cancer tissue than a drug of a lower molecular weight, i.e., an EPR effect. Thus, the PEG liposome is one important element in targeting the cancer tissues.
Recently, it has been attempted to cause a surface of a liposome to carry an antibody specifically recognizing a tissue or an organ, a part of an integrin, or a ligand molecule and targeting a tissue or an organ with active recognition. This is called active targeting. In the case of a liposome surface-modified with a polyethylene glycol chain for the purpose of extending the residence time in blood, active targeting is inhibited if the recognition site is concealed by the polyethylene glycol chain. Therefore, a recognition site is bound to a part of a terminus of the polyethylene glycol chain.
From the viewpoint of another aspect of the liposome, i.e., stability, the liposome, which is a molecular assembly, is in a metastable state physicochemically. The reason is that the liposome is prepared utilizing a phenomenon that amphiphilic molecules as a component of the liposome self-assembled by a hydrophobic interaction when being dispersed in water by some type of energy radiation. Therefore, the liposome may aggregate or fuse during storage, which may result in precipitation. In order to solve this, negative-charged lipid or cholesterol is mixed with lipids in a liposome in consideration of the stability in blood, and the surface of the liposome is modified with a polyethylene glycol chain or a glycochain. Therefore, the method of modifying the surface of the liposome with a polyethylene glycol chain is important. A lipid having a polyethylene glycol chain bound to diacylphosphatidylethanolamine or cholesterol is widely used. It has been reported that such a disacyl-type lipid having a polyethylene glycol chain bound thereto is released from a phospholipid bilayer vesicle (J. R. Silvius and M. J. Zuckermann, Biochemistry, 32, 3153, 1993; K. Sou, et al., Bioconjugate, 11, 372, 2000). The release rate of this lipid depends on the molecular weight of the polyethylene glycol chain and the size of the hydrophobic part (the number of carbons forming the acyl chain), i.e., the hydrophilic-hydrophobic balance. A lipid having a relatively large hydrophilic part is easier to be released. The present inventors developed a lipid including one polyethylene glycol chain and a great number of alkyl chains bound to each other using a monodendron structure, and obtained a series of amphiphilic molecules which are not easily released even when a polyethylene glycol chain having a large molecular weight is bound thereto (Japanese Patent No. 3181276).